Quinoline Compounds, Intermediates, Preparation Methods and Uses Thereof

ABSTRACT

A kind of quinoline compounds as formula A, pharmaceutical accepted solvates, optical isomers or polymorphisms thereof. The intermediates of formula D. in which, R 1 , R 2  and R 3  is independently H, halo or the subustitents of formula H, in which, R is H, halo, C 1 ˜C 4 alkyl, C 1 ˜C 4 alkoxyl. The preparation methods and the uses for the manufacture of a medicament of inhibiting the HMG CoA reductase and treating the diseases relating to the high blood fat. Compared with the fluvastatin, rosuvatatin, pitavastatin disclosed in the prior arts, present quinoline compounds have better activity of inhibiting HMG CoA reductase. Present quinoline compounds can be used for treating the diseases relating to the high blood fat.

FIELD OF THE TECHNOLOGY

The present invention pertains to the art of synthesis technology inmedicinal chemistry. More particularly, this invention is related tonovel quinoline compounds and their intermediates, preparation methodsand applications in pharmaceutical field.

BACKGROUND

Hypocholesterolemic agents have evolved rapidly whenhypercholesterolemia is well recognized as a primary risk factor inatherosclerotic diseases and coronary heart diseases. A class of drugs,such as 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase)inhibitors, the statins, are currently potent hypocholesterolemicagents. (Cai Z-Y, Zhou W-C. Progresses in researches of HMG CoAreductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22):1907-1911). The launched drugs, lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin, rosuvastatin, and pitavastatin are currentlyavailable hypocholesterolemic agents. However, as far as humanrequirement is concerned, there is a need to develop new potenthypocholesterolemic drugs.

The structure of the fully synthetic statins is characterized bydesmethylmevalonic acid or the lactone, the pharmacophore which isconnected to a lipophilic ring, such as hexahydronaphthalene, indole,pyrrole, pyrimidine, or quinoline. Systematical QSAR study on quinolinestatin compounds, such as pitavastatin, show desmethylmevalonic acidlinked through a trans-ethylene group to position 3 in quinolineexhibited good activity in inhibiting HMG CoA reductase. Theintroduction of chloro, methyl or methoxy etc. to the 6-, 7- or8-position of the quinoline nucleus may increase the inhibitory potency.(Cai Z-Y, Zhou W-C. Progresses in researches of HMG CoA reductaseinhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911). Sofar in the known quinolines as HMG CoA inhibitors, the aryl group suchas 4-fluorophenyl, is directly linked to position 4 in quinoline, thederivatives from 4-thiohenyl have not been reported.

SUMMARY OF THE DESCRIPTION

The present invention is directed to a quinoline compound of the formulaA, and its pharmaceutically acceptable solvate, stereoisomers orpolymorphism.

The present invention is also directed to the intermediate of theformula D.

Wherein

R₁, R₂ and R₃ are each independently selected from the group consistingof hydrogen, halogen, the group shown in formula H,

Wherein:

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkylor C1˜4 alkoxy.

The present invention is further directed to the preparation of thequinoline compound A, which are useful as inhibitors of HMG CoAreductase and useful in the treatment of the hypercholesterolemic. Ascompared with the drugs known in the art, such as fluvastatin,rosuvastatin or pitavastatin, the quinoline compound A of the presentinvention provides with more potent inhibition of HMG CoA reductase,which can be used to treat the related diseases of hypercholesterolemic.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates the general formula of Ethyl 4-substitutedthiophenyl-quinoline-3-carboxylate (E1˜4) according to PreparationExample 2;

FIG. 1B illustrates the data of yield, melting points (Mp.) and ¹H-NMRspectra of compound E1-4 according to Preparation Example 2;

FIG. 2A illustrates a general formula of Ethyl 7-chloro-4-substitutedthiophenyl-quinoline-3-carboxylate (E5˜8) according to PreparationExample 3;

FIG. 2B illustrates the data of yield, melting points (Mp.) and ¹H-NMRspectra of compound E5-8 according to Preparation Example 3;

FIG. 3A illustrates the general formula of Ethyl6-fluoro-7-chloro-4-substituted thiophenyl-quinoline-3-carboxylate(E9˜12) according to Preparation Example 4;

FIG. 3B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E9˜12 according to Preparation Example 4;

FIG. 4A illustrates the general formula of Ethyl6,7,8-trifluoro-4-substituted thiophenyl-quinoline-3-carboxylate(E13˜16) according to Preparation Example 5;

FIG. 4B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E13˜16 according to Preparation Example 5;

FIG. 5A illustrates the general formula of Ethyl 4,7-disubstitutedthiophenyl-quinoline-3-carboxylate (E17˜20) according to PreparationExample 6;

FIG. 5B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E17˜20 according to Preparation Example 6;

FIG. 6A illustrates the general formula of Ethyl6-fluoro-4,7-disubstituted thiophenyl-quinoline-3-carboxylate (E21˜24)according to Preparation Example 7;

FIG. 6B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E21˜24 according to Preparation Example 7;

FIG. 7A illustrates the general formula of Ethyl6,8-difluoro-4,7-disubstituted thiophenyl-quinoline-3-carboxylate(E25˜28) according to Preparation Example 8;

FIG. 7B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E E25˜28 according to Preparation Example 8;

FIG. 8A illustrates the general formula of Ethyl 4,6,7-trisubstitutedthiophenyl-quinoline-3-carboxylate (E29˜32) according to PreparationExample 9;

FIG. 8B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E29˜32 according to Preparation Example 9;

FIG. 9A illustrates the general formula of Ethyl6-fluoro-4,7,8-trisubstituted thiophenyl-quinoline-3-carboxylate(E33˜36) according to Preparation Example 10;

FIG. 9B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E33˜36 according to Preparation Example 10;

FIG. 10A illustrates the general formula of Ethyl4,6,7,8-tetrasubstituted thiophenyl-quinoline-3-carboxylate (E37˜40)according to Preparation Example 11;

FIG. 10B illustrates the data of yield, melting points (Mp.) and 1H-NMRspectra of compound E37˜40 according to Preparation Example 11;

FIG. 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, respectively,illustrate the general formula of Compounds F1˜40, which were preparedaccording to one of the methods in Preparation Example 12-17;

FIG. 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B illustrates thedata of yield, melting points (Mp.) and 1H-NMR spectra of CompoundsF1-40, which were prepared according to one of the methods inPreparation Example 12-17;

FIG. 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, respectively,illustrate the general formula of Compounds G1-40 and B1-40, which wereprepared according to Preparation Example 19 and Preparation Example 21;

FIG. 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B illustrates thedata of yield, and melting points (Mp.) of Compounds G1˜40 according toPreparation Example 19;

FIG. 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B also illustratesthe data of yield, and melting points (Mp.) of Compounds B1˜40 accordingto Preparation Example 21;

FIG. 31A, 33A, 35A, 37A, 39A, 41A, 43A, 45A, 47A, 49A respectivelyillustrates the general formula of Compounds D1-40, which were preparedaccording to Preparation Example 23;

FIG. 31B, 32, 33B, 34, 35B, 36, 37B, 38, 39B, 40, 41B, 42, 43B, 44, 45B,46, 47B, 48, 49B, 50 illustrates the data of yield, melting points (Mp.)and 1H-NMR spectra of Compounds D1˜40 according to Preparation Example23;

FIG. 51A, 53A, 55A, 57A, 59A, 61A, 63A, 65A, 67A, 69A respectivelyillustrates the general formula of Compounds A1-40, which were preparedaccording to one of the methods in Preparation Example 24-PreparationExample 29;

FIG. 51B, 52, 53B, 54, 55B, 56, 57B, 58, 59B, 60, 61B, 62, 63B, 64, 65B,66, 67B, 68, 69B, 70 illustrates the data of yield, melting points (Mp.)and 1H-NMR spectra of Compounds A1˜40 according to one of the methods inPreparation Example 12-17;

FIG. 71 illustrates in vitro inhibition on HMG CoA reductase of somequinoline compounds A (IC50).

DETAILED DESCRIPTION

The embodiments are illustrated by way of example and not limitation inthe figures of the accompanying drawings in which like referencesindicate similar elements.

An object of the present invention is directed to a novel quinolinecompound of the formula A, and its pharmaceutically acceptable solvate,stereoisomers or polymorphism that provide the HMG CoA reductaseinhibition activities and that can be used as hypocholesterolemicagents.

The quinoline compound of the formula A in this present invention isdesigned with pitavastatin as a leading compound. The pharmacophoremoiety, desmethylmevalonic lactone, is connected to position 3 in thequinoline nucleus, and the nucleus is flanked at position 4 bysubstituted thiophenyl as a lipophilic group, and at position 6, 7, 8 bydifferent group, such as substituted thiophenyl or halogen.

Wherein

R₁, R₂ and R₃ are each independently selected from the group consistingof hydrogen, halogen, the group shown in formula H,

Wherein

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkylor C1˜4 alkoxy.

The halogen in this invention is selected from the elements consistingof F, Cl, Br or I, and more preferred element is F or Cl. R is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred embodiment, the quinoline compound in thisinvention may be selected from the following:

-   (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-isopropylthiophenyl)quinoline-3-yl)-ethe    nyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxythiophenyl)quinoline-3-yl)-ethen    yl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(4,6,7,8-tetra-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(thiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(7-chloro-6-fluoro-4-(3-methoxythiophenyl)quinoline-3-yl)-et    henyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(4-isopropylthiophenyl)quinoline-3-yl)-ethen    yl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-t    etrahydro-4-hydroxy-2H-pyran-2-one;-   (4R,6S)-6-[(E)-2-(6-fluoro-4,7,8-tri-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one

Or

-   (4R,6S)-6-[(E)-2-(4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tet    rahydro-4-hydroxy-2H-pyran-2-one.

The pharmaceutically acceptable solvate in this invention is thehydrate, and solvate with C1˜4 alcohol or other organic solvents.

Another object of the present invention is directed to the intermediateof the formula D.

Wherein

R₁, R₂ and R₃ are each independently selected from the group consistingof hydrogen, halogen, the group shown in formula H,

Wherein

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkylor C1˜4 alkoxy.

The halogen in this invention is selected from the element consisting ofF, Cl, Br or I, and more preferred element is F or Cl. R is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, propoxy or isopropoxy.

A further object of the present invention is directed to the preparationof intermediate of the formula D, which is comprising that compound B isreacted with compound C, tert-butyl(3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate, byWittig-Horner reaction under basic condition in organic solvent.

Wherein

R₁, R₂ and R₃ are each independently selected from the group consistingof hydrogen, halogen, the group shown in formula H,

Wherein

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkylor C1˜4 alkoxy.

The compound B is prepared by the method shown in below:

Wherein R₁, R₂, R₃ and R are defined as the above. R₄, R₅ and R₆ areeach independently selected from the group consisting of hydrogen orhalogen.

The novel quinoline compound A is synthesized in optically pure forms bythe general method as follows:

1. Chlorination and Aromatic Nucleophilic Substitution

The monosubstituted or multisubstituted compounds of formula E areprepared with ethyl4-hydroxy-6,7,8-trisubstituted-quinoline-3-carboxylates as the startingmaterials by chlorination with POCl₃ and aromatic nucleophilicsubstitution under basic condition. The solvent in aromatic nucleophilicsubstitution is THF, EtOAc, toluene, DMF, or DMSO etc. The nucleophilesare the corresponding thiophenols. The base used in the reaction isselected from Et₃N, pyridine, Na₂CO₃, K₂CO₃, NaOH, NaH, and n-BuLi etc.The temperature of reaction is −30° C.˜150° C. The 4-monosubstituted,4,7-disubstituted, 4,7,8-trisubstituted or 4,6,7,8-tetrasubstitutedcompound of formula E is highly regiospecifically prepared underdifferent condition, such as different substrate, different mol ratio ofsubstrate and nucleophilic agents, base, solvent and reactiontemperature. Characterizations of compounds E are shown in Tables 1˜10.

2. Reduction

Compound F is prepared from compound E by reducing agents via reductionunder organic solvent. The organic solvent is selected from benzene,toluene, THF, methanol, ethanol etc. The organic solvent is alsoselected from the mixture of two solvents mentioned above. The reducingagent is selected from diisobutylaluminum hydride (DIBAL-H), KBH₄/ZnCl₂,LiAlH₄, LiAlH₄/LiCl, NaBH₄, NaBH₄/LiCl etc. The preferred organicsolvent is toluene. The optimal reducing agent is diisobutylaluminumhydride (DIBAL-H). The optimal reaction temperature is 0° C.˜20° C.Characterizations of compounds F are shown in Tables 11˜20.

3. Bromination:

Bromination of the compound F with PBr₃ affords the bromide G. Thesolvent for the reaction is selected from THF, t-BuOMe, CH₂Cl₂, CHCl₃,toluene etc, and the optimal solvent is CH₂Cl₂. The reaction temperatureis 0° C.˜100° C., and the optimal reaction temperature is 0° C.˜30° C.

4. Phosphorylation:

The compound G is converted to the corresponding phosphorus compound Bwith Ph₂POEt. The solvent is selected from THF, t-BuOMe, CH₂Cl₂, CHCl₃,toluene etc, and the preferred solvent is toluene. The reactiontemperature is 20□˜150□, and the optimal reaction temperature is 100°C.˜120° C. Characterizations of compound G and B are shown in Tables21˜30.

Wittig-Hornor reaction in this invention is the widely-known technology.The details of the Wittig-Hornor reaction in this invention are asfollows: compound B is reacted with compound C,tert-butyl-(3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoateunder basic condition in organic solvent. The solvent is selected fromTHF, Et₂O, t-BuOMe, toluene etc., and the optimal solvent is THF. Thealkaline is selected from lithium 2,2,6,6-tetramethylpiperidine, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, lithium n-butyl, NaHetc, and the optimal alkaline is lithium 2,2,6,6-tetramethylpiperidine.

The preferred conditions for the Wittig-Hornor reaction is that theoptimal reaction temperature is −100° C.˜50° C., and preferably between−78° C. and 25° C. The optimal reaction time was 20˜48 hours. The molratio of compound B, compound C and alkaline is 1:1:1˜1:2:4, and morepreferred is 1:1.2:1.5. Characterizations of compound D are shown inTables 31˜50.

Another object of the present invention is directed to the preparationof quinoline compound. The compound D is deprotected and lactonized withacid in solvent to give the target compounds A. The acid is selectedfrom CH₃COOH, CF₃COOH or HCl, and more preferred is CF₃COOH. The volumepercentage of the acid in solvent is 5˜40%, and more preferred is 20%.The optimal reaction temperature is 0° C.˜80° C., and more preferred is25° C. The optimal reaction time is 1˜8 hours. The solvent is selectedfrom one or more of THF, t-BuOMe, CH₂Cl₂, CHCl₃, toluene etc., and morepreferred is CH₂Cl₂ Characterizations of compound D are shown in Tables51˜70.

Yet another object of the present invention is directed to the quinolinecompound, and its pharmaceutically acceptable solvate, stereoisomers orpolymorphism which is prepared for inhibition of HMG CoA reductase anduseful in the treatment of the hypercholesterolemic.

The present invention provides pharmaceutical compositions whichcomprise quinoline compound A and any other pharmaceutically acceptablecarriers. The carriers include conventional drug carries in thepharmaceutical art, for instance, diluents or excipients such as water;binders such as cellulose derivatives, gelatin or polyvinylpyrrolidone,etc; fillers such as starch; disintegrants such as calcium carbonate orsodium bicarbonate. Additionally, other excipients such as essenceand/or sweetener can be included.

A variety of dosage forms can be prepared with the pharmaceuticalcompositions comprising quinoline compound A of the invention as activeingredients by conventional methods in the medical field. The soliddosage forms such as tablets, powders or capsules can be prepared fororal usage. The injection is prepared for injection usage. The contentof the compound A of the present invention in the formulation is0.1%˜99.9% (w/w), and more preferred is 0.5˜90% (w/w).

The dosage forms comprising quinoline compound A of the invention asactive ingredients may be prepared for intravenous injection,subcutaneous injection or oral usage, which can be administered topatients who need such therapy. The conventional dose is 1˜100mg/kg/day, according to the disease and patients' age.

The advantages of this invention are that: as compared with the drugsknown in the art, such as fluvastatin, rosuvastatin or pitavastatin, thequinoline compound A of the present invention is provided with morepotent in inhibiting HMG CoA reductase which can be used to treat therelated disease of hypercholesterolemic.

Other features of the invention will become apparent in the course ofthe following description of exemplary embodiments which are given forillustration of this invention and are not intended to be limitingthereof.

Preparation Example 1 Ethyl 4-chloro-6,7,8-trifluoroquinoline3-carboxylate

A solution of ethyl 4-hydroxy-6,7,8-trifluoroquinoline-3-carboxylate(59.0 g) and POCl₃ (500 ml) was refluxed for 8 h. Excess POCl₃ wasdistilled off, the residue was removed into the mixture of ice andwater. Solid NaHCO₃ was added into the mixture to pH 7˜8 and theprecipitated solid was isolated by filtration. The crude wasrecrystallized by toluene to afford the title compound (41.3 g, 65.6%yield), mp: 110-112° C.

ethyl 4-chloro-quinoline-3-carboxylate, ethyl6-fluoro-4,7-dichloroquinoline-3-carboxylate, and ethyl4,7-dichloro-quinoline-3-carboxylate, were prepared in the manneranalogous to the method described above, when ethyl4-hydroxy-quinoline-3-carboxylate, ethyl4-hydroxy-6-fluoro-7-chloro-quinoline-3-carboxylate, and ethyl4-hydroxy-7-chloro-quinoline-3-carboxylate were used as the startingmaterial respectively.

Preparation Example 2 Ethyl 4-substitutedthiophenyl-quinoline-3-carboxylate (E1˜4)

A mixture of ethyl 4-chloro-quinoline-3-carboxylate (8.0 g, 34 mmol),4-fluoro thiophenol (5.2 g, 41 mmol) and triethylamine (6.9 g, 68 mmol)in THF (80 mL) was stirred at room temperature for 30 min. The insolublematerial was filtered off. The filtrate was concentrated, and theresidue was recrystallized with toluene/petroleum ether to afford ethyl4-(4-fluoro-thiophenyl-quinoline-3-carboxylate (10.0 g, E2). Ethyl4-thiophenyl-quinoline-3-carboxylate (E1), ethyl4-(3-methoxy-thiophenyl-quinoline-3-carboxylate (E3), and ethyl4-(4-isopropyl-thiophenyl-quinoline-3-carboxylate (E4), were prepared inthe manner analogous to the method described above, when4-fluoro-thiophenol was replaced with thiophenol, 3-methoxy-thiophenol,and 4-isopropyl-thiophenol respectively. The data of yield, meltingpoints (Mp.) and ¹H-NMR spectra of compound E1-4 was shown in FIG. 1A,FIG. 1B.

Preparation Example 3 Ethyl 7-chloro-4-substitutedthiophenyl-quinoline-3-carboxylate (E5˜8)

Compounds of E5˜8 were prepared in the manner analogous to the method ofPreparation example 2, when ethyl 4,7-dichloro-quinoline-3-carboxylatewas reacted with thiophenol, 4-fluoro-thiophenol, 3-methoxy-thiophenol,and 4-isopropyl-thiophenol respectively. The data of yield, meltingpoints (Mp.) and ¹H-NMR spectra of compound E5-8 was shown in FIG. 2Aand FIG. 2B.

Preparation Example 4 Ethyl 6-fluoro-7-chloro-4-substitutedthiophenyl-quinoline-3-carboxylate (E9˜12)

Compounds of E9˜12 were prepared in the manner analogous to the methodof Preparation example 2, when ethyl6-fluoro-4,7-dichloro-quinoline-3-carboxylate was reacted withthiophenol, 4-fluoro-thiophenol, 3-methoxy-thiophenol, and4-isopropyl-thiophenol respectively. The data of yield, melting points(Mp.) and ¹H-NMR spectra of compound E9˜12 was shown in FIG. 3A and FIG.3B.

Preparation Example 5 Ethyl 6,7,8-trifluoro-4-substitutedthiophenyl-quinoline-3-carboxylate (E13˜16)

A solution of triethylamine (0.9 g, 8.6 mmol) in THF (60 ml) was droppedinto a mixture of ethyl 4-chloro-6,7,8-trifluoro-quinoline-3-carboxylate(5.0 g, 17.3 mmol), and 4-fluoro-thiophenol (2.2 g, 17.3 mmol) in THF(50 ml) at −15° C. The mixture was stirred for 1 h at this temperaturebefore quenching with water and ethyl acetate. The organic layer wasseparated, washed with brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by flash chromatography (silica gel, petroleumether-EtOAc, 10:1) to provide the title compound as a yellow solid, E14,(4.0 g, 60.0%). mp: 126-8° C.

Compounds E13, E15, and E16 were prepared in the manner similar to themethod described above, when 4-fluoro-thiophenol was replaced withthiophenol, 3-methoxy-thiophenol, and 4-isopropyl-thiophenolrespectively. The data of yield, melting points (Mp.) and ¹H-NMR spectraof compound E13˜16 was shown in FIG. 4A and FIG. 4B.

Preparation Example 6 Ethyl4,7-disubstituted-thiophenyl-quinoline-3-carboxylate (E17˜20)

3-Methoxythiophenol (10.8 g, 77 mmol) was added to a mixture of NaH(60%, 3.0 g, 75 mmol) in DMF (30 ml) at 0° C. The resulting mixture wasstirred at 0° C. for 0.5 h and then 4,7-dichloro-quinoline-3-carboxylate(7.0 g, 25.9 mmol) was added. The mixture was stirred at 60° C. for 0.5h. The reaction mixture was transferred to a separatory funnel. Ethylacetate and water were added. The organic layer was separated, washedwith brine, dried over Na₂SO₄, and concentrated. The resulting oil waspurified by silica gel chromatography (petroleum ether-EtOAc, 6:1) toprovide the title compound, E19, (10.9 g, 88.1%) as an oil.

Compounds E17, E18, and E20 were prepared in the manner similar to themethod described above, when 3-methoxy-thiophenol was replaced withthiophenol, 4-fluoro-thiophenol, and 4-isopropyl-thiophenolrespectively. The data of yield, melting points (Mp.) and ¹H-NMR spectraof compound E17˜20 were shown in FIG. 5A and FIG. 5B.

Preparation Example 7 Ethyl 6-fluoro4,7-disubstituted-thiophenyl-quinoline-3-carboxylate (E21˜24)

A mixture of ethyl 6-fluoro 4,7-dichloro-quinoline-3-carboxylate (6.0 g,20.8 mmol), 3-methoxy-thiophenol (5.8 g, 41.6 mmol) in DMF (20 ml) wasstirred at room temperature for 0.5 hour and then cooled to 0° C.Anhydrous K₂CO₃ (20.0 g, 145 mmol) was added into the mixture andstirred for 1 hour below 10° C. The solid was isolated by filtration andwashed with EtOAc. The filtrate was transferred to a separatory funnel,and ethyl acetate and water were added. The organic layer was separated,washed with brine, dried over Na₂SO₄, and concentrated. The resultingoil was purified by silica gel chromatography (petroleum ether-EtOAc,6:1) to provide the title compound, E23, (6.2 g, 60.0%) as oil.

Compounds E21, E22, and E24 were prepared in the manner analogous to themethod described above, when 3-methoxy-thiophenol was replaced withthiophenol, 4-fluoro-thiophenol, and 4-isopropyl-thiophenolrespectively. The data of yield, melting points (Mp.) and ¹H-NMR spectraof compound E21˜24 were shown in FIG. 6A and FIG. 6B.

Preparation Example 8 Ethyl6,8-difluoro-4,7-disubstituted-thiophenyl-quinoline-3-carboxylate(E25˜28)

About 7.7 ml Et₃N was added to a solution of ethyl6,7,8-trifluoro-4-chloro-quinoline-3-carboxylate (8.0 g, 27.4 mmol) and4-isopropylthiophenol (8.4 g, 55 mmol) in THF (80 ml) at roomtemperature and stirred for 1 hour. The insoluble materials werefiltered off, and the filtrate was evaporated in vacuum to give thecrude product. Recrystallization from petroleum ether gave the compound,E28, as a yellow solid (7.4 g, 50.0%), mp: 75-77° C.

Compounds E25, E26, and E27 were prepared in the manner analogous to themethod described above, when 4-isopropyl-thiophenol was replaced withthiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively.The data of yield, melting points (Mp.) and ¹H-NMR spectra of compoundE25˜28 were shown in FIG. 7A and FIG. 7B.

Preparation Example 9 Ethyl4,6,7-trisubstituted-thiophenyl-quinoline-3-carboxylate (E29˜32)

Ethyl 6-fluoro-4,7-dichloro-quinoline-3-carboxylate (7.1 g, 27.4 mmol)and 4-isopropyl-thiophenol (13.7 g, 90.1 mmol) were suspended in DMF (80ml). The mixture was heated to 60° C. and stirred until the material wasdissolved. Cooled to 25° C. and added to anhydrous K₂CO₃ (37.8 g, 274mmol), the mixture was stirred for 1 h at 25° C. The insoluble materialswere filtered off, and the filtrate was transferred to a separatoryfunnel, and ethyl acetate and water were added. The organic layer wasseparated, washed with brine, dried over Na₂SO₄, and concentrated todryness. The resulting oil was purified by silica gel chromatography(petroleum ether-EtOAc, 6:1) to provide the compound, E32, (14.9 g,83.5%) as oil.

Compounds E29, E30, and E31 were prepared in the manner analogous to themethod described above, when 4-isopropylthiophenol was replaced withthiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively.The data of yield, melting points (Mp.) and ¹H-NMR spectra of compoundE29˜32 were shown in FIG. 8A and FIG. 8B.

Preparation Example 10 Ethyl6-fluoro-4,7,8-trisubstituted-thiophenyl-quinoline-3-carboxylate(E33˜36)

Anhydrous K₂CO₃ (37.8 g, 274 mmol) was added to a mixture of ethyl6,7,8-trifluoro-4-chloro-quinoline-3-carboxylate (8.0 g, 27.4 mmol) and4-isopropyl-thiophenol (13.7 g, 90.1 mmol) in DMF (80 ml) at 25° C. andstirred for 1 h. The insoluble materials were filtered off, and thefiltrate was transferred to a separatory funnel, and ethyl acetate andwater were added. The organic layer was separated, washed with brine,dried over Na₂SO₄, and concentrated to dryness. The resulting oil waspurified by silica gel chromatography (petroleum ether-EtOAc, 6:1) toprovide the compound, E36, (13.0 g, 65.8%) as oil.

Compounds E33, E34, and E35 were prepared in the manner analogous to themethod described above, when 4-isopropylthiophenol was replaced withthiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively.The data of yield, melting points (Mp.) and ¹H-NMR spectra of compoundE33˜36 were shown in FIG. 9A and FIG. 9B.

Preparation Example 11 Ethyl4,6,7,8-tetrasubstituted-thiophenyl-quinoline-3-carboxylate (E37˜40)

A mixture of ethyl 6,7,8-trifluoro-4-chloro-quinoline-3-carboxylate (8.0g, 27.4 mmol), 4-isopropyl-thiophenol (18.7 g, 123.3 mmol), anhydrousK₂CO₃ (37.8 g, 274 mmol) in DMF (80 ml) was stirred at 60° C. for 1hour. The insoluble materials were filtered off, and the filtrate wastransferred to a separatory funnel and ethyl acetate and water wereadded. The organic layer was separated, washed with brine, dried overNa₂SO₄, and concentrated to dryness. The resulting oil was purified bysilica gel chromatography (petroleum ether-EtOAc, 6:1) to provide thetitle compound, E40, (19.4 g, 84.3%) as oil.

Compounds E37, E38, and E39 were prepared in the manner analogous to themethod described above, when 4-isopropylthiophenol was replaced withthiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively.The data of yield, melting points (Mp.) and ¹H-NMR spectra of compoundE37˜40 was shown in FIG. 10A and FIG. 10B.

Preparation Example 12 4-Thiophenyl-quinoline-3-methanol (F1)

A suspension of LiAlH₄(1.0 g, 29.4 mmol) and anhydrous LiCl (1.2 g, 29.4mmol) in anhydrous THF (30 ml) was stirred for 0.5 h under an atmosphereof nitrogen at 0° C. The solution of E1 (3.2 g, 9.8 mmol) in anhydrousTHF (10 ml) was added into the resulting suspension at 0° C. and stirredfor 2 h before adding Na₂SO₄.10H₂O slowly. The insolubable material wasfiltered. The filtrate was concentrated, and the residue was purified bysilica gel chromatography (petroleum ether-EtOAc, 2:1) to provide thetitle compound (0.28 g, 10%).

Preparation Example 13 4-(4-Fluoro-thiophenyl) quinoline-3-methanol (F2)

A mixture of anhydrous ZnCl₂ (2.9 g, 21.4 mmol) and KBH₄ (2.3 g, 42.8mmol) in THF (15 ml) was stirred at room temperature for 2 h. A solutionof E2 (3.5 g, 10.7 mmol) in toluene (75 ml) was added and refluxed (95°C.) overnight. The reaction mixture was cooled to room temperature, theinsoluble was filtered off, and the filter cake was washed with hottoluene. All the toluene was combined and washed with water, 0.1 mol/LNaOH, brine, dried over Na₂SO₄, and concentrated to dryness. Theresulting oil was purified by silica gel chromatography (petroleumether-EtOAc, 1:1) to provide the title compound F2 (0.3 g, 9.8%).

Preparation Example 14 4-(3-methoxy-thiophenyl)quinoline-3-methanol (F2)

NaBH₄ (1.2 g, 31.7 mmol) was added into a solution of E3 (5.0 g, 15.3mmol) in EtOH (100 ml) at room temperature and stirred for 8 h. Theinsoluble material was filtered and the filtrate was concentrated todryness. The residue was purified by silica gel chromatography(petroleum ether-EtOAc, 1:1.5) to provide the title compound F3 (1.3 g,30%).

Preparation Example 15 7-Chloro-4-(4-fluoro-thiophenyl)quinoline-3-methanol (F6)

Anhydrous LiCl (0.14 g, 3.3 mmol) was added into a solution of E6 (1.0g, 2.6 mmol) in EtOH (15 ml) and stirred for 5 min. at 0° C. NaBH₄ (0.13g, 3.4 mmol) was added into the resulting mixture and stirred for 0.5 hat 0° C. The reaction mixture was stirred for 18 h at room temperaturebefore concentration to dryness. Water and EtOAc was added to theresidue and the organic layer was separated, washed with brine, driedover Na₂SO₄ and concentrated. The residue was purified by silica gelchromatography (petroleum ether-EtOAc, 1:1) to provide the titlecompound F6 (0.27 g, 30%).

Preparation Example 16 6,7,8-trifluoro-4-thiophenyl-quinoline-3-methanol(F13)

About 22 ml (55 mmol) of a 2.5 mol/L DIBAL-H in toluene was added to asolution of E13 (8.0 g, 21.9 mmol) in anhydrous toluene (80 ml) at 0° C.under an atmosphere of nitrogen. The resulting solution was stirred for2 h at 0° C. before quenching with 6 mol/L HCl. The mixture was added toEtOAc and the organic layer was separated, washed with water, dried overNa₂SO₄ and concentration. Recrystallization from 95% ethanol to give thetitle compound as a solid (5.0 g, 70.6%), mp: 126-128° C.

Preparation Example 17 Preparation of Compounds F1˜40

Compounds, F1˜40, were prepared in the manner similar to the method ofPreparation example 16, when Compounds E1˜40 were used as the materialrespectively. The data of yield, melting points (Mp.) and ¹H-NMR spectraof compounds F1˜40 were shown in FIG. 11-20.

Preparation Example 186,7,8-Trifluoro-4-thiophenyl-3-bromomethyl-quinoline (G13)

A solution of PBr₃ (8.4 g, 31 mmol) in CH₂Cl₂ (40 ml) was added to themixture of F13 (5.0 g, 15.5 mmol) in CH₂Cl₂ (30 ml) at 0° C. Theresulting mixture was stirred for 10 minutes at 0° C. and then for 2hour at room temperature before quenching with a saturated aqueousNaHCO₃ solution to pH 8. The mixture was added to CH₂Cl₂ and the organiclayer was separated, washed with water, dried over Na₂SO₄, andconcentrated to obtain the title compound (5.2 g, 86.8%), mp: 98-100° C.which was used without further purification.

Preparation Example 19 Preparation of Compounds G1˜40

Compounds G1˜40 were prepared in the manner similar to the method ofPreparation example 18, when Compounds F1˜40 were used as the materialrespectively. The data of yield, and melting points (Mp.) of compoundsG1˜40 were shown in FIG. 21˜30.

Preparation Example 20 6,7,8-Trifluoro-4-thiophenyl-3(diphenylphosphorylmethyl)-quinoline (B13)

A solution of G13 (5.2 g, 13.4 mmol) and ethyl diphenylphosphinite (6.2ml, 27 mmol) in toluene (25 ml) was refluxed for 2 h during which timethe precipitated solid developed. After cooling to room temperature, thesolid was isolated by filtration and washed with toluene. The productwas then dried to obtain the title compound (6.6 g, 96.9% yield), mp:244-245° C.

Preparation Example 21 Preparation of Compounds B1˜40

Compounds B1˜40 were prepared in the manner similar to the method ofPreparation example 20, when Compounds G1˜40 were used as the materialrespectively. The data of yield and melting points (Mp.) of compoundsG1˜40 were shown in FIG. 21˜30.

Preparation Example 22 tert-Butyl(3R,5S,6E)-7-[6,7,8-trifluoro-4-thiophenyl-quinoline-3-yl]-3,5-dihydroxy-3,5-O-isopropylidene-6-heptenoate(D13)

1.2 ml (3 mmol) of 2.5 mol/L hexane solution of n-BuLi was added to asolution of 2,2,6,6-tetramethylpiperidine (0.5 g, 3 mmol) in anhydrousTHF (10 ml) at 0° C. and stirred for 15 minutes under an atmosphere ofnitrogen. B13 (1.0 g, 2.0 mmol) was added to the resulting solution at0° C. and stirred for 1 hour at room temperature. Compound C (0.61 g,2.4 mmol) in anhydrous THF (2 ml) was added to the solution and stirredfor overnight before quenching with saturated aqueous NaHCO₃ solution(20 ml) at 0° C. The resulting mixture was added to EtOAc and theorganic layer was separated, washed with brine, dried over Na₂SO₄ andconcentrated. The resulting oil was purified by silica gelchromatography (petroleum ether-EtOAc, 5:1) to provide the titlecompound (0.6 g, 55.8%) as a solid, mp: 169-171° C.

Preparation Example 23 Preparation of Compounds D1˜40

Compounds D1˜40 were prepared in the manner similar to the method ofPreparation example 22, when Compounds B1˜40 were used as materialrespectively. The data of yield, melting points (Mp.) and ¹H-NMR spectraof compounds D1˜40 were shown in FIG. 31˜50.

Preparation Example 24(4R,6S)-6-[(E)-2-(4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A1)

A solution of D1 (0.44 g, 0.86 mmol) and CF₃COOH (2 ml, 25.8 mmol) inCH₂Cl₂ (10 ml) was stirred at 0° C. for 8 h before quenching with asaturated aqueous NaHCO₃ solution. The mixture was added to EtOAc andthe organic layer was separated, washed with water, dried over Na₂SO₄,and concentrated. The resulting oil was purified by silica gelchromatography (petroleum ether-EtOAc, 2:1) to provide the titlecompound (0.30 g, 91.7%) as white solid. mp: 102-104° C.

Preparation Example 25(4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A13)

A solution of D13 (0.47 g, 0.86 mmol) and CF₃COOH (2 ml, 25.8 mmol) inCH₂Cl₂ (10 ml) was stirred at 80° C. for 1 h before quenching with asaturated aqueous NaHCO₃ solution. The mixture was added to EtOAc andthe organic layer was separated, washed with water, dried over Na₂SO₄,and concentrated. The resulting oil was purified by silica gelchromatography (petroleum ether-EtOAc, 2:1) to provide the titlecompound (0.30 g, 81.4%) as white solid. mp: 177-178° C.

Preparation Example 26(4R,6S)-6-[(E)-2-(4-(4-fluoro-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A2)

A solution of D2 (0.86 mmol) and concentrated HCl (4 ml) in t-BuOMe (10ml) was stirred at 25° C. for 8 h before quenching with a saturatedaqueous NaHCO₃ solution. The mixture was added to EtOAc and the organiclayer was separated, washed with water, dried over Na₂SO₄, andconcentrated. The resulting oil was purified by silica gelchromatography (petroleum ether-EtOAc, 2:1) to provide the titlecompound.

Preparation Example 27(4R,6S)-6-[(E)-2-(4-(3-methoxy-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A3)

A solution of D3 (0.86 mmol) and CH₃COOH (0.5 ml) in CHCl₃ (10 ml) wasstirred at 30° C. for 4 h before quenching with a saturated aqueousNaHCO₃ solution. The mixture was added to EtOAc and the organic layerwas separated, washed with water, dried over Na₂SO₄, and concentrated.The resulting oil was purified by silica gel chromatography (petroleumether-EtOAc, 2:1) to provide the title compound.

Preparation Example 28(4R,6S)-6-[(E)-2-(4-(4-isopropyl-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A4)

A solution of D4 (0.86 mmol) and CH₃COOH (0.5 ml) in toluene (10 ml) wasstirred at 30° C. for 3 h before quenching with a saturated aqueousNaHCO₃ solution. The mixture was added to EtOAc and the organic layerwas separated, washed with water, dried over Na₂SO₄, and concentrated.The resulting oil was purified by silica gel chromatography (petroleumether-EtOAc, 2:1) to provide the title compound.

Preparation Example 29 Preparation of Compound of A1˜A40

Compounds A1˜40 were prepared in the manner similar to the method ofPreparation example 24, when Compounds D1˜40 were used as materialrespectively. The data of yield, melting points (Mp.) and ¹H-NMR spectraof compounds A1˜40 were shown in FIG. 51˜70.

Efficacy Example HMG CoA Reductase Inhibition Assay of Some QuinolineCompounds A In Vitro

The HMG CoA reductase inhibitory activity of compounds A in vitro wasassayed following the method of “Kim H J et al: Characterization ofβ-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor from Puerariathunbergiana, J Agric Food Chem 2005, 53:5882-5888”.

The HMG CoA reductase was extracted from the liver of MaleHoltzman-Sprague-Dawley rats. The positive control experiment was madewith rosuvastatin, pitavastatin, atorvastatin, and fluvastatin. Thenegative control experiment was made without any inhibitor. The blankcontrol experiment was made without HMG CoA and inhibitor.3-Hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase catalyzes thereduction of 1 mol HMG CoA and 2 mol NADPH to afford mevalonic acid andNADP. NADPH shows a maximum absorption at 340 nm, and NADP shows noabsorption at 340 nm. The reduction rate determined in this study wasmeasured by the descending rate of ultraviolet absorption value at 340nm. After addition of the inhibitor, the inhibitory activity ofinhibitor on the enzyme can be calculated by the difference ofultraviolet absorption value. The in vitro HMG CoA reductase inhibitionof some quinoline compounds in the invention was assayed by the methoddescribe above.

The concentration of an inhibitor required to inhibit 50% of the HMG CoAreductase under the above assay conditions was defined as IC50. The UVabsorbance was measured in eight levels for each sample. A statisticalanalysis was performed by standard curve using mean values of triplicatemeasurements (n=3). The results were seen in FIG. 71.

The data of FIG. 71 showed that some quinoline compounds in thisinvention were more potent than fluvastatin, rosuvastatin orpitavastatin in HMG CoA reductase inhibition.

1. A quinoline compound of formula A, and the pharmaceuticallyacceptable solvate, the stereoisomer or polymorphism thereof,

Wherein R₁, R₂ and R₃ are independently selected from the groupsconsisting of hydrogen, halogen, the group shown in formula H,

Wherein R is selected from the group consisting of hydrogen, halogen,C1˜4 alkyl or C1˜4 alkoxy.
 2. An intermediate of the formula D,

Wherein R₁, R₂ and R₃ are independently selected from the groupconsisting of hydrogen, halogen, the group shown in formula H,

Wherein R is selected from the group consisting of hydrogen, halogen,C1˜4 alkyl or C1˜4 alkoxy.
 3. The compound according to claim 1 or 2,wherein halogen is F or Cl.
 4. The compound according to claim 1 or,2wherein R is methyl, ethyl, propyl, isopropyl, cyclepropyl, methoxy,ethoxy, propoxy, or isopropoxy.
 5. A quinoline compound, and itspharmaceutically acceptable solvate, stereoisomer or polymorphismaccording to claim 1, is selected from:(4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(4,6,7,8-tetra-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(thiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(7-chloro-6-fluoro-4-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;(4R,6S)-6-[(E)-2-(6-fluoro-4,7,8-tri-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one;or(4R,6S)-6-[(E)-2-(4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.6. The quinoline compound, and its pharmaceutically acceptable solvate,stereoisomer or polymorphism according to claim 1, wherein thepharmaceutically acceptable solvate is hydrate, C1˜4 alcohol or otherorganic solvates.
 7. A method of preparation of the intermediate offormula D according to claim 2, wherein compound B is reacted withcompound C, tert-butyl(3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate, byWittig-Horner reaction under basic condition in organic solvent.

Wherein R₁, R₂ and R₃ are independently selected from the groupconsisting of hydrogen, halogen, the group shown in formula H,

Wherein R is selected from the group consisting of hydrogen, halogen,C1˜4 alkyl or C1˜4 alkoxy.
 8. A method of preparation of the quinolinecompound, and its pharmaceutically acceptable solvate, stereoisomer orpolymorphism according to claim 1, wherein compound D reacts under acidcondition.
 9. The method of the preparation according to claim 8,wherein the acid is CF₃COOH, CH₃COOH or HCl.
 10. The method of thepreparation according to claim 8, wherein the volume percentage of acidin solvent is 5˜40%.
 11. The method of the preparation according toclaim 10, wherein the volume percentage of acid in solvent is 20%. 12.The method according to claim 8, wherein the temperature is 0° C.˜80° C.13. The method according to claim 12, wherein the temperature is 25° C.14. The method according to claim 8, wherein the reaction time isbetween 1-8 hours.
 15. The method according to claim 8, wherein thesolvent is selected from one or more of the following: THF, t-BuOMe,CH₂Cl₂, CHCl₃, and toluene.
 16. The quinoline compound, and itspharmaceutically acceptable solvate, stereoisomer or polymorphismaccording to claim 1 is applied for the preparation for inhibition ofHMG CoA reductase and treatment of the diseases related tohyperlipidemia.